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Introduction: Ectopic thymic tissue can arise as an asymptomatic neck mass, which may be detected on imaging studies. The aim of this study was to determine the incidence of ectopic thymic tissue in paediatric FNAs and to the correlate clinical, radiological and cytomorphological findings. Methods: FNAs in children with neck and mediastinal lesions performed between January 2012 and July 2016 were reviewed for cases of ectopic thymus. These were then evaluated and correlated with the cytology findings. Results: Of 739 FNAs, 13 (1.8%) cases from 11 patients showed ectopic thymic tissue. The targeted lesions were in the thyroid (n = 7), submandibular region (n = 1), superior mediastinum (n = 1) and paratracheal region (n = 1). The most common indication was for microcalcifications concerning for papillary thyroid carcinoma on ultrasound (n = 6). Imaging findings included fusiform lesions with linear and punctuate bright echoes. The cytology evaluation showed small lymphocytes with discohesive epithelioid cells in most cases, and proteinaceous fluid in the cystic case. There were rare macrophages and Hassall's corpuscles. Flow cytometry and/or immunostains were performed in all cases, supporting thymic origin. Conclusion: Ectopic thymic tissue is rarely present as a neck mass or thyroid nodule on FNA biopsy. The ultrasound imaging findings reveal a well‐defined fusiform lesion with punctate bright echoes that could be misinterpreted as papillary thyroid carcinoma. The aspirates show a small lymphoid population, immunophenotypically compatible with thymic T‐cells, in addition to scattered epithelial cells. Therefore, knowledge of the typical ultrasonographic and cytopathological features can help make a definitive diagnosis and avoid more invasive procedures in paediatric patients. [ABSTRACT FROM AUTHOR]

J Oral Pathol Med (2012) Kaposi sarcoma (KS), an AIDS defining condition, remains one of the most commonly HIV-associated neoplasms. While the use of highly active antiretroviral therapy (HAART) has brought about a dramatic decrease in the prevalence and incidence of AIDS-KS worldwide, this has not been the case in resource-poor sub-Saharan African countries, where HIV has reached epidemic proportions and human herpesvirus-8 infection is endemic. Oral involvement is a common manifestation of AIDS-associated KS and may be an early presenting finding of HIV infection. The clinical manifestation of oral KS can vary and may have an unpredictable course ranging from mild to fulminant. Rapidly progressive facial lymphoedema associated with extensive advanced oral KS portends a poor prognosis. Oral KS may regress with antiretroviral therapy or may flare up as part of the immune reconstitution inflammatory syndrome. The oral lesions of AIDS-KS are best managed with HAART together with systemic chemotherapy. This article provides a review of contemporary knowledge of the biology, pathology, clinical features and management of oral AIDS-KS. [ABSTRACT FROM AUTHOR]

Summary Ticks are effective vectors of viral, bacterial, rickettsial and parasitic diseases. Many of the tick-borne diseases (TBDs) are of significance to transfusion medicine, either because of the risks they pose to the blood supply or the necessity for blood products required in their treatment. The transmission of tick-borne pathogens via blood transfusion is of global concern. However, among transfusion medicine practitioners, experience with most of these microorganisms is limited. Transfusion transmission of TBDs has been documented largely by means of single case reports. A better understanding of the epidemiology, biology and management of this group of diseases is necessary in order to assess the risks they pose to the blood supply and to help guide effective prevention strategies to reduce this risk. Unique methods are required to focus on donor selection, predonation questioning, mass screening and inactivation or eradication procedures. The role of the transfusion medicine service in their treatment also needs to be better defined. This article reviews the growing body of literature pertaining to this emerging field of transfusion medicine and offers some recommendations for transfusionists in dealing with TBDs. [ABSTRACT FROM AUTHOR]

Presents an update on issues related to hematology as of March 2001. Relationship between transient abnormal myelopoiesis and acute megakaryoblastic leukemia in Down's syndrome; Bone marrow morphology in human immunodeficiency virus-infected South Africans with and without tuberculosis; Leucopenia in professional football players.

The article focuses on the study of glypican 3 (GPC3) immunohistochemistry in the fetal ovary, normal ovary and a subset of ovarian tumours. The study found out the reliability of GPC3 as a biomarker for ovarian germ cell tumours showing extra-embryonic differentiation along vitelline or trophoblastic pathways. It also noted the significance of determining the potential role of the protein in ovarian development as well as in the diagnosis and treatment of ovarian germ cell tumours.

A letter to the editor is presented in response to the article about lymphangiectatic and lymphangioma-like KS, two lymphoedematous variants of Kaposi's sarcoma.

The author reflects on the use of digital imaging for cytopathology. The author considers digital imaging in the pathological field as a disruptive innovation. It states that digital imaging process involves images storage, acquisition, sharing and editing. The author also mentions that as technology gets more cost effective, digital pathology becomes a commoner and that digital imaging's benefits have been increasingly realized.

A letter to the editor is presented in response to "Localized Kaposi's sarcoma in a patient with pemphigus vulgaris," by P. Avalos-Peralta, A. Herrera, J.J. Rios-Martin, A.M. Perez-Bernal, D. Moreno-Ramirez, and F. Camacho, in the 2006 issue of "Journal of European Academy of Dermatology and Venereology."

Background: Human Granulocytic Ehrlichiosis (HGE) and Human Monocytic Ehrlichiosis (HME) are emergent tick-borne diseases in the United States. The agent of HGE is transmitted by the tick vector Ixodes dammini, which is the same vector for the Lyme disease spirochete Borrelia burgdorferi and Babesia microti. Patients with HGE and HME may have signs and symptoms that mimic TTP, including thrombocytopenia, renal failure, fever, altered mental status and rare schistocytes. There have been no reported studies to determine what proportion of patients presenting with TTP/HUS may have undiagnosed ehrlichiosis, or concurrent Lyme disease or babesiosis suggesting exposure to ticks that may carry ehrlichial agents. This study was undertaken to screen patients with TTP/HUS for possible underlying tick-borne infections. Methods: Frozen stored serum collected prior to initial plasmapheresis from 10 adult patients (3 males, 7 females; mean age 44 years) diagnosed with TTP/HUS was tested. For all specimens, exposure to the agents of HGE and HME was determined by indirect immunofluorescence assay (IFA) for IgM and IgG antibodies. For positive individuals, polymerase chain reaction (PCR) and rodent inoculation were performed on whole blood to directly demonstrate ehrlichial agents. IgG antibodies for B. microti were also determined by IFA. An enzyme-linked immunosorbent assay, with western blot confirmation for equivocal or positive results, was used to diagnose Lyme disease. Results: Two patients had positive test results (see table). All other patients were negative by these tests. Conclusions: Ehrlichiosis should be considered in the differential diagnosis of TTP/HUS in regions known to be endemic for this infection. Our findings indicate that a small proportion (20%) of our patients from an endemic area for ticks appear to have had prior tick-borne infections. Their TTP/HUS illness, however, appears not to be associated with an acute tick-borne infection because these patients were IgM and PCR negative. [ABSTRACT FROM AUTHOR]

Discusses the case of a 73-year-old male patient diagnosed with acute Babesia microti infection. Disease background of babesiosis; Percent parasitemia in Wright-Giemsa stained blood smear; Acquisition of disease via platelet transfusion.

Background: Thoracic switch/sucrose nonfermentable-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4)-deficient (SD) malignancies, including SD undifferentiated tumor (SD-UT) and SD non-small cell lung carcinoma (SD-NSCLC), have been recently described. The cytologic features of these neoplasms in fine-needle aspiration (FNA) and effusion specimens have rarely been reported in the literature. This study aimed to describe and compare the spectrum of cytologic, immunohistochemical, and clinical features of these high-grade malignancies recently encountered at the participating institutions., Methods: This study documented clinical and imaging characteristics of tumors from 27 patients. Sixteen cytomorphologic features and immunohistochemical findings were compared between SD-UT and SD-NSCLC samples., Results: Twenty three FNAs, two bronchial brushings, and two pleural fluids were evaluated, including 17 SD-UT cases (mean patient age, 70 years) and 10 SD-NSCLC cases (mean patient age, 62 years). Both malignancies presented with large thoracic masses and/or hilar/mediastinal lymphadenopathy. All SD-UT cytologic samples had a discohesive or mixed cohesive-discohesive architecture, and most (13 of 17) showed predominant rhabdoid or mixed rhabdoid-epithelioid features. Most SD-NSCLC cytologic samples (nine of 10) were either cohesive or mixed cohesive-discohesive and had a predominantly epithelioid morphology (eight of 10). Keratins and claudin-4 were negative or focally positive in SD-UT samples, whereas they were diffusely positive in SD-NSCLC samples. Both malignancies were negative for TTF-1 and p40/p63 and showed loss of expression of SMARCA4., Conclusions: Although there is considerable clinical and cytopathologic overlap between SD-UT and SD-NSCLC, some key features allow for their distinction. SD-UT is mostly discohesive with rhabdoid or mixed rhabdoid-epithelioid features, whereas SD-NSCLC often has cohesive epithelioid morphology. The combination of clinical presentation, cytomorphology, and immunohistochemistry is essential for a definitive diagnosis., (© 2024 The Author(s). Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Artificial intelligence (AI)-based systems are transforming cytopathology practice. The aim of this study was to evaluate the sensitivity of high-grade squamous intraepithelial lesion (HSIL) Papanicolaou (Pap) diagnosis assisted by the Hologic Genius Digital Diagnostics System (GDDS)., Methods: A validation study was performed with 890 ThinPrep Pap tests with the GDDS independently. From this set, a subset of 183 cases originally interpreted as HSIL confirmed histologically were included in this study. The sensitivity for detecting HSIL by three cytopathologists was calculated., Results: Most HSIL cases were classified as atypical glandular cell/atypical squamous cell-high grade not excluded (AGC/ASC-H) and above by all cytopathologists. Of these cases, 11.5% were classified as low-grade squamous intraepithelial lesion (LSIL) by pathologist A (P-A), 6% by pathologist B (P-B), and 5.5% by pathologist C (P-C); 3.8%, 2.7%, and 1.6% of these cases were classified as atypical squamous cell of unknown significance (ASC-US) by P-A, P-B, and P-C, respectively. The sensitivity for detection of cervical intraepithelial neoplasia 2 and above (CIN2+) lesions was 100% if ASC-US and above (ASC-US+) abnormalities were counted among all three pathologists. The sensitivity for detection of CIN2+ lesions was 84.7%, 91.3%, and 92.9% by P-A, P-B, and P-C, respectively, for ASC-H and above abnormalities. The Kendall W coefficient was 0.722, which indicated strong agreement between all pathologists., Conclusions: New-generation AI-assisted Pap test screening systems such as the GDDS have the potential to transform cytology practice. In this study, the GDDS aided in interpreting HSIL in ThinPrep Pap tests, with good sensitivity and agreement between the pathologists who interacted with this system., (© 2024 The Author(s). Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: The authors previously developed an artificial intelligence (AI) to assist cytologists in the evaluation of digital whole-slide images (WSIs) generated from bile duct brushing specimens. The aim of this trial was to assess the efficiency and accuracy of cytologists using a novel application with this AI tool., Methods: Consecutive bile duct brushing WSIs from indeterminate strictures were obtained. A multidisciplinary panel reviewed all relevant information and provided a central interpretation for each WSI as being "positive," "negative," or "indeterminate." The WSIs were then uploaded to the AI application. The AI scored each WSI as positive or negative for malignancy (i.e., computer-aided diagnosis [CADx]). For each WSI, the AI prioritized cytologic tiles by the likelihood that malignant material was present in the tile. Via the AI, blinded cytologists reviewed all WSIs and provided interpretations (i.e., computer-aided detection [CADe]). The diagnostic accuracies of the WSI evaluation via CADx, CADe, and the original clinical cytologic interpretation (official cytologic interpretation [OCI]) were compared., Results: Of the 84 WSIs, 15 were positive, 42 were negative, and 27 were indeterminate after central review. The WSIs generated on average 141,950 tiles each. Cytologists using the AI evaluated 10.5 tiles per WSI before making an interpretation. Additionally, cytologists required an average of 84.1 s of total WSI evaluation. WSI interpretation accuracies for CADx (0.754; 95% CI, 0.622-0.859), CADe (0.807; 95% CI, 0.750-0.856), and OCI (0.807; 95% CI, 0.671-0.900) were similar., Conclusions: This trial demonstrates that an AI application allows cytologists to perform a triaged review of WSIs while maintaining accuracy., (© 2024 American Cancer Society.)

Background: Differentiated high-grade thyroid carcinoma (DHGTC) is recently recognized by the World Health Organization (WHO) as a subgroup of thyroid carcinomas with high-grade features while retaining the architectural and/or cytologic features of well-differentiated follicular-cell-derived tumors. The cytomorphology of DHGTC is not well documented despite potential implications for patient triage and management., Methods: The pathology archives of six institutions were searched for cases diagnosed on resection as "high-grade thyroid carcinoma" using WHO criteria. The fine-needle aspiration (FNA) cohort represents a 10-year period (2013-2023); all were reviewed to confirm DHGTC classification. The corresponding FNAs were assessed for 32 cytomorphologic features., Results: Forty cases of DHGTC with prior FNA were identified. The mean patient age was 64.2 years. The average lesion size was 4.9 cm, and the majority demonstrated a TI-RADS score of 4 or 5 (95.2%). Three main high-grade subsets of DHGTC based on corresponding histology included papillary thyroid carcinoma (65%), follicular carcinoma (22.5%), and oncocytic carcinoma (12.5%). Over 97% of FNA cases were classified as Bethesda category IV or above. Approximately 25% of DHGTC showed cytologic features that included marked cytologic atypia, increased anisonucleosis, large oval nuclei, mitotic activity, or necrosis (p < .05); 68% of DHGTC cases were associated with high-risk molecular alterations. TERT mutations occurred in 41%, of which 89% of these were associated with a second mutation, usually RAS or BRAF p.V600E., Conclusions: Cytology has a low sensitivity for DHGTC, although a subset of DHGTCs have cytologic features raising the possibility of a high-grade thyroid carcinoma. Other findings include high-risk molecular changes and clinicopathologic features such as older patient age and larger lesion size., (© 2024 American Cancer Society.)

Background: The presurgical evaluation of cervical lymph nodes (CLNs) in the management of thyroid malignant lesions is crucial for the extent of surgery or detection of metastases. In these last decades, fine-needle aspiration cytology (FNAC) has been shown to have a central role in the detection of nodal thyroid metastases. It is adopted for the possibility of confirming suspected metastases either in the presurgical phase or in the follow-up of patients after thyroidectomy. However, FNAC from CLNs can be challenging, especially in cystic lesions. In this regard, the combination of FNAC with thyroglobulin measurement in the eluate from FNAC (Tg-FNAC) seems to increase the sensitivity of FNAC in the detection of CLN metastases. The role of FNAC and Tg-FNAC was investigated in this series., Methods: One hundred fifty-three prospective cytological samples of CLNs were studied along with surgical follow-up in the period between 2020 and 2022. Immunocytochemistry (ICC) was performed on liquid-based cytology-stored material., Results: One hundred fifty-nine enlarged CLNs included 19 central lymph nodes and 140 CLNs. Forty-two thyroidal CLN metastases and 117 reactive lymph nodes were found. Thirty-one CLN dissections were performed in patients with a previous diagnosis of thyroid carcinoma (mostly papillary thyroid carcinoma [PTC]), whereas 128 CLNs with a concomitant suspicious and/or malignant thyroid nodule were found. There was one false-positive case among all the malignant histologically confirmed cases, and two of 117 reactive CLNs (1.7%) had a diagnosis of metastatic PTC. Markedly high Tg-FNAC was found in all metastatic CLNs, including 11 cystic metastatic CLNs detected by Tg-FNAC with a negative FNAC. ICC (including Tg, CK-19, and LCA) recognized nine cases with low Tg-FNAC and scant suspicious thyrocytes. Tg-FNAC plus FNAC diagnosed 94.2% of malignancies., Conclusions: FNAC represents a valid method for the evaluation of CLNs, especially combined with ICC. Tg-FNAC is an additional method with a useful role in FNAC., (© 2023 American Cancer Society.)

Background: TP53 gene plays a major role in the negative control of cell proliferation and in the regulation of signaling cascades. TP53 mutation may have a relevant role in the malignant transformation of thyroid cells as well as thyroid tumor progression. TP53 mutation has been detected only in few well differentiated thyroid carcinomas and is absent in benign conditions., Methods: A total of 162 prospective thyroid cytology and corresponding histological samples diagnosed from atypia of indeterminate significance (AUS) to malignant, were studied via immunocytochemistry for p53. Hence, 50 benign lesions (B) were used as negative control. Molecular analysis for p53 only was performed., Results: The cytology resulted in 50 B, 48 AUS, 40 follicular neoplasms (FNs), 23 suspicious for malignancy (SFM), and 1 malignant (M) case. The authors reported 102 negative and 60 positive p53 cases. The 60 positive cases included 27 cases with weak and/or focal cytoplasmic positivity (+1) and 33 with cases moderate (2+) to strong (3+) cytoplasmic and/or nuclear expression. Overall, 71 cases had histology (2 B, 11 AUS, 37 FN, 20 SFM, and 1 M) including 61.7% benign and 38.2% malignant diagnoses. Only 16 of 71 (5 FN, 10 SFM, and 1 M) were p53-positive. Furthermore, 100% AUS and 86.5% FN cases were p53-negative, none of which had malignant histology. All p53-positive cases were associated with a larger nodule size, tall-cell variant subtype, multifocality, extra thyroidal infiltration, and nodal metastases. Noninvasive follicular thyroid neoplasm with papillary like nuclear features were negative for p53. Few discrepancies in p53 intensity were observed on histology; there were no differences with the molecular testing., Conclusions: p53 might be useful in discriminating thyroid follicular lesions. p53 is likely to be a useful diagnostic marker in recognizing indeterminate lesions that are well-differentiated thyroid cancers., (© 2023 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Introduction: The diagnosis of metastatic prostatic cancer (MPC) by fine needle aspiration (FNA) can usually be rendered by typical cytomorphologic and immunohistochemical (IHC) features. However, MPC diagnosis may be complicated by transformation to atypical phenotypes such as small cell carcinoma, typically under pressure from androgen deprivation therapy (ADT). Predictive and prognostic biomarkers can also be assessed by IHC. This study illustrates how careful assessment of cytologic and biomarker features may provide therapeutic and prognostic information in MPC., Design: We reviewed our anatomic pathology archives for MPC diagnosed by FNA from January 2014 to June 2021. Clinical histories, cytology slides, and cell blocks were reviewed. Extensive IHC biomarker workup was performed, including markers of prostate lineage, cell-cycle dysfunction, Ki-67, neuroendocrine markers, PDL1, and androgen receptor splice variant 7. Cases were reclassified into three categories: conventional type, intermediary type, and high-grade neuroendocrine carcinoma (HGNC)., Results: Eighteen patients were identified. Twelve had conventional MPC, including six of six ADT-naive patients. Six of twelve (50%) with prior ADT were reclassified as intermediary or HGNC. Four intermediary cases included two with squamous differentiation and two with pro-proliferative features. Two HGNC cases had typical small cell carcinoma cytomorphology. Expression of PDL1 was identified in two cases and ARv7 in three cases. Five of five intermediary and HGNC patients died of disease versus six of eleven with with conventional type., Conclusions: Aggressive cytomorphologic variants were commonly identified in patients with prior ADT. Identification of nonconventional cytomorphology and increased proliferation can provide important prognostic information. Recognition of these changes is important for an accurate diagnosis, and the identification of high-grade variants can affect therapeutic decision-making. Clinically actionable biomarkers such as PDL1 and ARv7 can be assessed by IHC., (© 2022 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Data on Afirma's genomic sequencing classifier (GSC) performance in atypia of undetermined significance (AUS) subcategories is limited. This study investigated GSC performance in AUS nodules with architectural atypia (AUS-A), cytological atypia (AUS-C), architectural and cytological atypia (AUS-AC), and predominantly Hürthle cells (AUS-HC)., Methods: This study retrieved consecutive thyroid nodules having a recurrent cytologic diagnosis of AUS with qualifiers and a concurrent GSC diagnostic result. All nodules were followed by either surgical intervention or clinical and/or ultrasound monitoring (≥6 months). GSC benign call rate (BCR), rate of histology-proven malignancy, and diagnostic parameters of GSC were calculated for individual AUS subcategories. Statistical analysis was performed using the Fisher exact test., Results: A total of 135 AUS nodules fulfilled inclusion criteria, including 79 AUS-A, 9 AUS-C, 29 AUS-AC, and 18 AUS-HC. BCR was 72.2%, 66.7%, 44.8%, and 77.8% in AUS-A, AUS-C, AUS-AC, and AUS-HC, respectively. AUS-A showed a greater BCR than AUS-AC (p &lt; .05). All GSC-benign nodules were considered benign on clinical or surgical follow-up. Among GSC-suspicious nodules, histology-proven malignancies represented 4.5% of AUS-A, 0% of AUS-C, 56.3% of AUS-AC, and 25.0% of AUS-HC cases. AUS-AC demonstrated a higher malignant rate compared with AUS-A (p &lt; .05). GSC offers 100% NPV and a wide range (5%-56%) of PPV across all AUS subcategories. AUS-AC demonstrated a greater PPV compared with AUS-A (p &lt; .05)., Conclusion: BCR of GSC and malignant rates associated with suspicious GSC may differ in various AUS subcategories. GSC-suspicious nodules with both architectural and cytologic atypia are more likely to be malignant. These findings may improve clinical triage and/or management of patients with AUS thyroid nodules., (© 2022 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Secretory carcinoma (SC) of the salivary gland is a rare entity with limited published literature on cytomorphology. The authors present the largest cohort to date of SC fine-needle aspiration (FNA) cases., Methods: FNA cases of histologically confirmed SC were retrospectively retrieved from 12 academic institutions in the United States, Italy, Finland, and Brazil. The collated data included patient demographics, imaging findings, cytopathologic diagnoses according to the Milan System for Reporting Salivary Gland Cytopathology, cytomorphologic characteristics, and immunohistochemical/molecular profiles., Results: In total, 40 SCs were identified (male-to-female ratio, 14:26) in patients with a mean age of 52 years (age range, 13-80 years). Ultrasound imagining revealed a hypoechoic, ovoid, poorly defined, or lobulated mass. The most common primary site was the parotid gland (30 of 40 tumors). Regional lymph node metastasis (9 patients) and distant metastasis (4 patients; brain, liver, lungs, and mediastinum) were noted. Two patients died of disease. FNA smears were cellular and demonstrated mainly large, round cells with intracytoplasmic vacuoles or granules and round-to-oval nuclei with smooth nuclear contour, minimal irregularities, and prominent nucleoli arranged predominantly in clusters, papillary formations, and single cells. The background was variable and contained inflammatory cells, mucin, or proteinaceous material. The diagnoses were malignant (19 of 38 tumors; 50%), suspicious for malignancy (10 of 38 tumors; 26%), salivary gland neoplasm of uncertain malignant potential (7 of 38 tumors; 18%), and atypia of undetermined significance (2 of 38 tumors; 6%) according to the Milan System for Reporting Salivary Gland Cytopathology. Two malignant cases (2 of 40 tumors; 5%) were metastases. The neoplastic cells were immunoreactive for S100 (23 of 24 tumors), mammaglobin (18 of 18 tumors), GATA-3 (13 of 13 tumors), AE1/AE3 (7 of 7 tumors), and vimentin (6 of 6 tumors). ETV6-NTRK3 fusion was detected in 32 of 33 tumors by fluorescence in situ hybridization (n = 32) and next-generation sequencing (n = 1)., Conclusions: Familiarity with cytomorphologic features and the immunohistochemical/molecular profile of SC can enhance diagnostic accuracy., (© 2022 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Pediatric salivary gland fine-needle aspiration (FNA) is uncommon with a higher frequency of inflammatory lesions and a small proportion of malignancies. This international, multi-institutional cohort evaluated the application of the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) and the risk of malignancy (ROM) for each diagnostic category., Methods: Pediatric (0- to 21-year-old) salivary gland FNA specimens from 22 international institutions of 7 countries, including the United States, England, Italy, Greece, Finland, Brazil, and France, were retrospectively assigned to an MSRSGC diagnostic category as follows: nondiagnostic, nonneoplastic, atypia of undetermined significance (AUS), benign neoplasm, salivary gland neoplasm of uncertain malignant potential (SUMP), suspicious for malignancy (SM), or malignant. Cytology-histology correlation was performed where available, and the ROM was calculated for each MSRSGC diagnostic category., Results: The cohort of 477 aspirates was reclassified according to the MSRSGC as follows: nondiagnostic, 10.3%; nonneoplastic, 34.6%; AUS, 5.2%; benign neoplasm, 27.5%; SUMP, 7.5%; SM, 2.5%; and malignant, 12.4%. Histopathologic follow-up was available for 237 cases (49.7%). The ROMs were as follows: nondiagnostic, 5.9%; nonneoplastic, 9.1%; AUS, 35.7%; benign neoplasm, 3.3%; SUMP, 31.8%; SM, 100%; and malignant, 100%. Mucoepidermoid carcinoma was the most common malignancy (18 of 237; 7.6%), and it was followed by acinic cell carcinoma (16 of 237; 6.8%). Pleomorphic adenoma was the most common benign neoplasm (95 of 237; 40.1%)., Conclusions: The MSRSGC can be reliably applied to pediatric salivary gland FNA. The ROM of each MSRSGC category in pediatric salivary gland FNA is relatively similar to the ROM of each category in adult salivary gland FNA, although the reported rates for the different MSRSGC categories are variable across institutions., (© 2022 American Cancer Society.)

Cytology effusions are often the only material available for diagnosing malignant pleural mesothelioma (MPM). However, the cytomorphological features alone are not always diagnostic, and cytology samples preclude an assessment for pleural tissue invasion. Accordingly, immunohistochemical, soluble, and molecular biomarkers have been developed. The aim of this study is to provide quantitative evidence regarding the diagnostic performance of novel biomarkers. To that end, a systematic literature review was performed of articles dealing with a loss of BRCA1-associated protein 1 (BAP1), methylthioadenosine (MTAP), 5-hydroxymethylcitosine (5-hmC), glucose transporter 1 (GLUT1), insulin like-growth factor II messenger RNA-binding protein 3 (IMP3), enhanced zeste homologue 2 (EZH2) staining, cyclin-dependent kinase inhibitor 2A (CDKN2A) homozygous deletion (HD) testing, soluble mesothelin, and microRNA quantification in cytological samples for the diagnosis of MPM versus reactive atypical mesothelial cells. Sensitivity and specificity were extracted, and a meta-analysis was performed. The quality of the studies was assessed with Quality Assessment of Diagnostic Accuracy Studies 2, and the quality of the evidence was evaluated with the Grading of Recommendations Assessment, Development, and Evaluation approach. Seventy-one studies were included. BAP1 loss showed a sensitivity of 0.65 (confidence interval [CI], 0.59-0.71) and a specificity of 0.99 (CI, 0.93-1.00). MTAP loss and p16 HD showed 100% specificity with sensitivities of 0.47 (CI, 0.38-0.57) and 0.62 (CI, 0.53-0.71), respectively. BAP1 loss and CDKN2A HD combined showed maximal specificity and a sensitivity of 0.83 (CI, 0.78-0.89). GLUT1 and IMP3 showed sensitivities of 0.82 (CI, 0.70-0.90) and 0.65 (CI, 0.41-0.90), respectively, with comparable specificity. Mesothelin showed a sensitivity of 0.73 (CI, 0.68-0.77) and a specificity of 0.90 (CI, 0.84-0.93). In conclusion, some of the recently emerging biomarkers are close to 1.00 specificity. Their moderate sensitivity on their own, however, can be significantly improved by the use of 2 biomarkers, such as a combination of BAP1 and CDKN2A with fluorescence in situ hybridization or a combination of BAP1 and MTAP immunohistochemistry., (© 2021 American Cancer Society.)

Background: Programmed death-ligand 1 (PD-L1) expression with combined positive score (CPS) ≥1 is required for administration of checkpoint inhibitor therapy in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). The 22C3 pharmDx Dako immunohistochemical assay is the one approved as companion diagnostic for pembrolizumab, but many laboratories work on other platforms and/or with other clones, and studies exploring the potential interchangeability of assays have appeared., Evidence From the Literature: After review of the literature, it emerges that the concordance among assays ranges from fair to moderate, with a tendence of assay SP263 to yield a higher quota of positivity and of assay SP142 to stain better immune cells. Moreover, pathologists achieve very good concordance in assessing PD-L1 CPS, particularly with SP263., Conclusions: Differences in terms of platforms, procedures, and study design still preclude a quantitative synthesis of evidence and clearly further work is needed to draw stronger conclusions on the interchangeability of PD-L1 assays in HNSCC., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Mutational analysis contributes to the diagnosis and prognosis of thyroid nodules analyzed with fine-needle aspiration cytology (FNAC). Although several advanced molecular tests based on multiple molecular markers are available for clinical use and have increased their impact on clinical management of patients, they are not widely available. Among them is BRAF V600E, one of the most studied mutations. Other genetic alterations, such as TERT promoter mutations, may coexist in thyroid carcinomas. Previous studies have demonstrated that this duet might be involved in the aggressiveness of thyroid cancer, although its prognostic value related to mortality remains undefined. The detection of such genetic alterations in thyroid liquid-based cytology (LBC) thus may assist with patient management., Methods: From January 2013 to June 2014, 356 thyroid FNAC samples were processed by LBC, including 174 surgical follow-up samples. BRAF V600E and TERT mutation analyses were performed on both LBC and histopathology., Results: The study included 119 samples categorized as atypia of undetermined significance, 42 categorized as follicular neoplasms, 61 categorized as suspicious for malignancy, and 34 categorized as positive for malignancy. BRAF V600E mutation was detected in 10.4% of all cases, whereas TERT promoter mutations were identified in 1.1%. TERT-mutated cases belonged to the positive for malignancy category, with a histologic diagnosis of tall cell variant of papillary thyroid carcinoma. These genetic alterations correlated with lymph node metastases (P = .0349) and higher disease stage., Conclusions: BRAF V600E and TERT analysis can be performed on LBC. TERT mutations are rarely identified in well differentiated thyroid carcinoma but are associated with higher stage. Although a larger molecular panel may offer more information, analyzing these few point mutations is still likely to be useful for managing potentially more aggressive thyroid carcinomas., (© 2021 American Cancer Society.)

Thyroid tumors can be classified into epithelial, nonepithelial, and nonprimary lesions. Nonepithelial thyroid tumors are rare. They can be of primary origin within the thyroid gland, arise secondary to contiguous growth from adjacent tissues, or represent metastatic disease. The incidence of nonepithelial tumors of the thyroid is only 1% to 2%, most of which are lymphomas; the remainder includes mesenchymal and histiocytic tumors. This review examines the cytohistological features of various nonepithelial and nonlymphoid tumors of the thyroid, including vascular lesions, neural tumors (including granular cell tumor and paraganglioma), smooth muscle tumors, solitary fibrous tumor, histiocytic neoplasms (eg, Langerhans cell histiocytosis and Rosai-Dorfman disease), and follicular dendritic cell sarcoma. Their differential diagnosis is discussed, including recommendations to prevent the pitfall of mistaking these rare tumors for more common epithelial thyroid neoplasms., (© 2020 American Cancer Society.)

Malignant mesothelioma is a rare malignancy with a poor prognosis whose development is related to asbestos fiber exposure. An increasing role of genetic predisposition has been recognized recently. Pleural biopsy is the gold standard for diagnosis, in which the identification of pleural invasion by atypical mesothelial cell is a major criterion. Pleural effusion is usually the first sign of disease; therefore, a cytological specimen is often the initial or the only specimen available for diagnosis. Given that reactive mesothelial cells may show marked atypia, the diagnosis of mesothelioma on cytomorphology alone is challenging. Accordingly, cell block preparation is encouraged, as it permits immunohistochemical staining. Traditional markers of mesothelioma such as glucose transporter 1 (GLUT1) and insulin-like growth factor 2 mRNA-binding protein 3 (IMP3) are informative, but difficult to interpret when reactive proliferations aberrantly stain positive. BRCA1-associated protein 1 (BAP1) nuclear staining loss is highly specific for mesothelioma, but sensitivity is low in sarcomatoid tumors. Cyclin-dependent kinase inhibitor 2A (CDKN2A)/p16 homozygous deletion, assessed by fluorescence in situ hybridization, is more specific for mesothelioma with better sensitivity, even in the sarcomatoid variant. The surrogate marker methylthioadenosine phosphorylase (MTAP) has been found to demonstrate excellent diagnostic correlation with p16. The purpose of this review is to provide an essential appraisal of the literature regarding the diagnostic value of many of these emerging biomarkers for malignant mesothelioma in effusion cytology., (© 2021 American Cancer Society.)

Background: Thyroid paragangliomas are extremely rare and often are misdiagnosed by preoperative fine-needle aspiration (FNA) because their cytologic features overlap with those of other thyroid neoplasms. The objective of this study was to review the cytomorphology in a series of thyroid paragangliomas and correlate the findings with histopathology., Methods: Five thyroid paraganglioma cases that underwent FNA were reviewed. Their clinical presentation, radiology features, cytomorphology, ancillary tests, and histopathology were analyzed., Results: All patients were women with an average age of 49 years (age range, 35-61 years) and presented with an asymptomatic, solitary thyroid nodule. Radiologically, these nodules (size range, 1.8-3.0 cm) were well circumscribed, hypoechoic, and hypervascular. FNA smears showed clusters of loosely cohesive, medium-to-large epithelioid cells with clear-to-eosinophilic and occasionally foamy cytoplasm that had indistinct cytoplasmic borders. The nuclei were round to oval with focal nuclear membrane irregularities, inconspicuous nucleoli, focal marked anisonucleosis, and occasional intranuclear pseudoinclusions. Naked nuclei, variable numbers of plasmacytoid cells, multinucleated giant cells, and sustentacular cells were present in the background along with blood vessels and lymphocytes. Cytology diagnoses were incorrect and included follicular neoplasm (n = 4) and follicular lesion of undetermined significance (n = 1). Final histopathology with immunohistochemistry revealed conventional paraganglioma (n = 3) or sclerosing paraganglioma with invasive features (n = 2)., Conclusions: All thyroid paragangliomas were misdiagnosed on FNA as follicular neoplasms, in part because of the rarity of these tumors in this location and cytomorphology mimicking follicles. The absence of colloid, the presence of naked nuclei, focal marked anisonucleosis, and the presence of sustentacular cells are important cytology clues., (© 2020 American Cancer Society.)

Background: High-grade transformation (HGT) is a rare process whereby conventional low- to intermediate-grade salivary gland carcinomas (SGC) transform into high-grade, poorly or undifferentiated malignancies with focal or complete loss of their conventional histomorphologic features. Because tumors with HGT are associated with a worse prognosis than their conventional counterparts, preoperative recognition of HGT may be of benefit for optimal patient management. Using a multi-institutional approach, we describe the largest fine needle aspiration (FNA) cohort of salivary gland carcinomas with HGT., Methods: The archives of 9 large academic medical centers were searched, and 22 cases of SGC with HGT were identified by surgical excision accompanied by preoperative FNA. Clinical and cytomorphologic features were retrospectively reviewed., Results: The male-to-female ratio was 14:8, and the mean patient age was 60.2 years. The average tumor size was 3.6 cm, and 19 cases were from the parotid gland. Acinic cell carcinoma with HGT was the most common tumor subtype, comprising 12 cases with HGT, followed by adenoid cystic carcinoma, secretory carcinoma, and other subtypes. Eighteen cases were classified as malignant; however, a specific diagnosis of HGT was not made. Sixteen cases contained a high-grade cytologic component, and 7 cases had a mixture of both conventional and high-grade components retrospectively., Conclusions: SGC with HGT should be considered in the differential diagnosis of a salivary gland aspirate exhibiting high-grade cytomorphologic features. The presence of distinct tumor populations, conventional and high-grade, should prompt consideration of HGT, especially when the conventional component is acinic cell carcinoma or adenoid cystic carcinoma., (© 2020 American Cancer Society.)

Background: Cystic salivary gland lesions present diagnostic challenges on fine-needle aspiration (FNA) specimens that are related to sampling limitations and a broad differential diagnosis. This study evaluated the benefit of applying the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) to a series of cystic salivary gland lesions., Methods: The pathology archives at the Johns Hopkins Hospital were searched to identify cystic salivary gland FNA specimens over a 19-year period (2000-2018). Patient demographics, cytomorphologic features, and clinical and surgical follow-up were recorded. The MSRSGC was applied to the cases. The risk of malignancy (ROM) and the risk of neoplasia (RON) were calculated for each category., Results: One hundred seventy-eight cases were identified (96 males and 82 females) with a mean age of 53 years (range, 4-90 years). After the MSRSGC was applied, there were 52 nondiagnostic cases (29.2%), 80 nonneoplastic cases (44.9%), 35 cases of atypia of undetermined significance (AUS; 19.7%), 3 benign neoplasms (1.7%), 3 salivary gland neoplasms of uncertain malignant potential (SUMP; 1.7%), 4 cases suspicious for malignancy (SFM; 2.2%), and 1 malignant case (0.6%). One hundred fifty-six of the 178 patients (87.6%) had follow-up data available. The RON and ROM values for cases with surgical follow-up were 33.3% (3 of 9) and 22.2% (2 of 9) for the nondiagnostic category, 42.9% (9 of 21) and 19% (4 of 21) for the nonneoplastic category, 76.5% (13 of 17) and 29.4% (5 of 17) for the AUS category, 100.0% (2 of 2) and 50.0% (1 of 2) for the SUMP category, and 100% (2 of 2) and 100% (2 of 2) for the SFM category, respectively., Conclusions: Applying the MSRSGC to cystic salivary gland lesions improves patient management by preventing unnecessary surgery for nonneoplastic conditions. The ROM was highest in the SFM category (100%), which was followed by the SUMP, AUS, nondiagnostic, and nonneoplastic categories. Less than adequate specimens may increase the diagnosis of AUS., (© 2020 American Cancer Society.)

Background: The Ki-67 index is important for grading neuroendocrine tumors (NETs) in cytology. However, different counting methods exist. Recently, augmented reality microscopy (ARM) has enabled real-time image analysis using glass slides. The objective of the current study was to compare different traditional Ki-67 scoring methods in cell block material with newer methods such as ARM., Methods: Ki-67 immunostained slides from 50 NETs of varying grades were retrieved (39 from the pancreas and 11 metastases). Methods with which to quantify the Ki-67 index in up to 3 hot spots included: 1) "eyeball" estimation (EE); 2) printed image manual counting (PIMC); 3) ARM with live image analysis; and 4) image analysis using whole-slide images (WSI) (field of view [FOV] and the entire slide)., Results: The Ki-67 index obtained using the different methods varied. The pairwise kappa results varied from no agreement for image analysis using digital image analysis WSI (FOV) and histology to near-perfect agreement for ARM and PIMC. Using surgical pathology as the gold standard, the EE method was found to have the highest concordance rate (84.2%), followed by WSI analysis of the entire slide (73.7%) and then both the ARM and PIMC methods (63.2% for both). The PIMC method was the most time-consuming whereas image analysis using WSI (FOV) was the fastest method followed by ARM., Conclusions: The Ki-67 index for NETs in cell block material varied by the method used for scoring, which may affect grade. PIMC was the most time-consuming method, and EE had the highest concordance rate. Although real-time automated counting using image analysis demonstrated inaccuracies, ARM streamlined and hastened the task of Ki-67 quantification in NETs., (© 2020 American Cancer Society.)

Background: Sclerosing pneumocytoma (SP) is a rare, benign pulmonary neoplasm. To the authors' knowledge, the current study is the first to evaluate the cytomorphology and immunoprofile of SP in a series., Methods: A total of 9 fine-needle aspiration cases of SP (7 of which were computed tomography guided and 2 of which were endobronchial ultrasound guided) including histopathology and immunohistochemistry were collected from 5 institutions., Results: The female-to-male ratio was 3.5:1, and the mean age of the patients was 54 years (range, 27-73 years). All cases presented as lung nodules, with a mean size of 2.2 cm (range, 1.1-5 cm), and were interpreted as atypical on rapid on-site evaluation. The final diagnoses were favor adenocarcinoma (1 case), well-differentiated lung adenocarcinoma (2 cases), low-grade epithelial neoplasm (2 cases), and sclerosing pneumocytoma (4 cases). Samples were moderately cellular, and consisted of round epithelioid cells with clear cell features, columnar cells, and spindle cells. A papillary arrangement with prominent hyalinized fibrovascular cores was the most common architectural pattern, followed by flat sheets and acinar formations. Tumor cells demonstrated mild, focally moderate nuclear pleomorphism with prominent nucleoli, hyperchromasia, nuclear elongation, nuclear overlap, and occasional nuclear inclusions and grooves. The background consisted of foamy macrophages (9 cases), hemosiderin pigment (6 cases), and lymphoid aggregates (3 cases) with no mitoses and/or necrosis. The surface cells and underlying round cells were positive for both thyroid transcription factor 1 and epithelial membrane antigen in all cases, which was the most notable immunohistochemical finding., Conclusions: Cytomorphological findings of SP overlap with those of well-differentiated lung adenocarcinoma. Awareness of these cytomorphologic findings and the distinct immunoprofile of the 2 cell types found in SP should prevent a misdiagnosis and aggressive treatment., (© 2020 American Cancer Society.)

Background: A peritheliomatous pattern (PP) in tumors is characterized by a sheath of viable tumor cells closely surrounding a central blood vessel. In the authors' cytology practice, such a PP has been recognized in several metastatic melanoma specimens. The aim of this study was to evaluate the frequency of a PP in cytology samples of melanoma in comparison with other tumors., Methods: Eighty archival fine-needle aspiration (FNA) cases of metastatic melanoma were compared with 65 control cases (35 poorly differentiated/metastatic carcinomas, 15 lymphomas, and 15 recurrent/metastatic/high-grade sarcomas). Cytologic findings were correlated with corresponding histologic specimens, which were available for 44 cases (55%) in the melanoma group and for 23 cases (35.38%) in the control group. All slides were examined for a PP and were semiquantitatively graded for comparison., Results: A PP was present in 51.3% of the cytologic preparations (n = 41) among the melanoma group cases, whereas in the control group, a PP was present in only 3.1% of the cases (n = 2). A PP was present in 65.9% of melanomas with available histologic sections (n = 29) and in 8.7% of tissue samples from the control group (n = 2). A PP was seen more often in cell blocks than direct smear preparations (51.3% vs 40.0%) from patients with melanoma., Conclusions: The presence of a characteristic PP can be helpful in diagnosing melanoma in FNA samples because it was present in almost half of the metastatic melanoma cases in this study and was rarely present in other tumor types. A PP is easier to recognize and more often presents in cell blocks than aspirate smears. Ancillary studies such as immunohistochemistry are helpful for excluding other entities that may exhibit a PP., (© 2020 American Cancer Society.)

Background: Programmed death-ligand 1 (PD-L1) expression is emerging as an important predictive biomarker in anti-PD-L1 cancer immunotherapy. Its role has been clearly defined in various human cancers and is linked to a poor prognosis and resistance to anticancer therapies. The role of PD-L1 in thyroid cancers has not been well defined in fine-needle aspiration cytology (FNAC). The authors examined the performance of PD-L1 immunostaining in liquid-based cytology (LBC) to determine whether it could be a biomarker of malignancy or aggressive disease., Methods: From January 2018 to March 2019, 236 thyroid lesions, which had been diagnosed by FNAC as indeterminate lesions, suspicious for malignancy (SFM), and malignant, were enrolled. PD-L1 immunostaining was performed on both LBC and corresponding histology samples., Results: The FNAC cohort included 50 benign negative controls, 42 samples of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), 33 samples of follicular neoplasm/suspicious for follicular neoplasm (FN/SFN), 53 samples that were suspicious for malignancy (SFM), and 58 malignant samples. AUS/FLUS samples included 3 goiters, 32 follicular adenomas (FAs), 1 noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), 5 invasive follicular variants of papillary thyroid carcinoma (I-FVPTCs), and 1 follicular carcinoma; whereas FN/SFN samples included 24 FAs and 9 malignancies (4 I-FVPTCs, 1 NIFTP, 3 papillary thyroid carcinomas [PTCs], and 1 oncocytic follicular carcinoma). The 53 SFM samples were diagnosed on histopathology as 2 FAs, 5 NIFTPs, 15 I-FVPTCs, and 31 PTCs; whereas the 58 malignant specimens included 5 NIFTPs, 5 I-FVPTCs, and 48 PTCs. Increased plasma membrane and cytoplasmic PD-L1 expression was found in 79 cases (38.5%), including 61 PTCs (conventional and variants). Negative PD-L1 expression was found in NIFTPs and FAs. A BRAF V600E mutation was identified in 15% of PD-L1-positive malignancies., Conclusions: The current data suggest that PD-L1 expression in the thyroid gland might represent a marker of malignancy that correlates with PTC, but not with NIFTP. Thyroid neoplasms with PD-L1 expression also ae enriched with BRAF V600E mutations, suggesting that they are associated with more aggressive behavior., (© 2019 American Cancer Society.)

Many studies have examined the diagnostic concordance of whole slide imaging (WSI) and light microscopy (LM) for surgical pathology. In cytopathology, WSI use has been more limited, mainly because of technical issues. The aim of this study was to review the literature and determine the overall diagnostic concordance of WSI and LM in cytopathology. A systematic search of PubMed, Scopus, and the Cochrane Library was performed, with data extracted from the included articles. A quality assessment of studies was performed with a modified Quality Assessment of Diagnostic Accuracy Studies 2 tool. The primary outcome was concordance for the diagnoses rendered by WSI and LM as shown by the concordance rate with the original diagnosis, intra-observer and interobserver concordance with the κ coefficient, or a percentage. Secondary outcomes included the time taken to reach a diagnosis and the quality and perception of WSI. A descriptive survey was provided. Among 1867 publications, a total of 19 studies (1%) were included. Overall, the concordance between WSI and the original diagnosis was 84.1%, the intra-observer concordance between WSI and LM was 92.5% with a κ coefficient of 0.66, and the interobserver κ coefficient was 0.69. The time to reach a diagnosis was longer with WSI in all studies. The quality of WSI was good, but diagnostic confidence and cytologist preference were higher for LM. In conclusion, the concordance of WSI with LM is acceptable and in line with systematic reviews in surgical pathology. However, the time required for scanning and technical issues represent barriers to complete adoption. It is foreseeable that technical advances and rigorous validation study design will help to improve the diagnostic concordance of WSI with LM in cytopathology., (© 2019 American Cancer Society.)

Background: Unlike Papanicolaou tests, there are no commercially available computer-assisted automated screening systems for urine specimens. Despite The Paris System for Reporting Urinary Cytology, there still is poor interobserver agreement with urine cytology and many cases in which a definitive diagnosis cannot be made. In the current study, the authors have reported on the development of an image algorithm that applies computational methods to digitized liquid-based urine cytology slides., Methods: A total of 2405 archival ThinPrep glass slides, including voided and instrumented urine cytology cases, were digitized. A deep learning computational pipeline with multiple tiers of convolutional neural network models was developed for processing whole slide images (WSIs) and predicting diagnoses. The algorithm was validated using a separate test data set comprised of consecutive cases encountered in routine clinical practice., Results: There were 1.9 million urothelial cells analyzed. An average of 5400 urothelial cells were identified in each WSI. The algorithm achieved an area under the curve of 0.88 (95% CI, 0.83-0.93). Using the optimal operating point, the algorithm's sensitivity was 79.5% (95% CI, 64.7%-90.2%) and the specificity was 84.5% (95% CI, 81.6%-87.1%) for high-grade urothelial carcinoma., Conclusions: The authors successfully developed a computational algorithm capable of accurately analyzing WSIs of urine cytology cases. Compared with prior studies, this effort used a much larger data set, exploited whole slide-level and not just cell-level features, and used a cell gallery to display the algorithm's output for easy end-user review. This algorithm provides computer-assisted interpretation of urine cytology cases, akin to the machine learning technology currently used for automated Papanicolaou test screening., (© 2019 American Cancer Society.)

Certain carcinomas of the thyroid gland behave aggressively resulting in increased patient morbidity and poor patient prognosis. The diagnosis of these aggressive thyroid cancer subtypes is sometimes challenging and subject to increased interobserver variability. This review deals with the cytological features of such tumors including aggressive variants of papillary thyroid carcinoma, poorly differentiated thyroid carcinoma, and anaplastic thyroid carcinoma. These malignancies fall into 2 groups based on their cytomorphology: those that exhibit distinct microscopic features (eg, nuclear findings typical of classical papillary thyroid carcinoma or marked anaplasia) and those that present with more subtle cytologic features (eg, nuclear pseudostratification, "soap bubble" nuclei, supranuclear or subnuclear cytoplasmic vacuoles, rosette-like structures, hobnail cells). We review the literature regarding these aggressive thyroid cancers and highlight important phenotypic characteristics that can be useful for their diagnosis based on fine needle aspiration., (© 2019 American Cancer Society.)

Background: Hyalinizing trabecular tumors (HTTs) are rare, essentially benign, follicular cell-derived thyroid neoplasms characterized by a trabecular growth pattern and nuclear pseudoinclusions. Their cytological findings are misleading, because these tumors are often misinterpreted on fine needle aspirate cytology as malignant lesions, such as papillary thyroid cancer and/or medullary thyroid cancer, leading to unnecessary total thyroidectomy. The aim of this study was to analyze the cytomorphological features and application of ancillary techniques in a series of HTTs., Methods: Of 26 histological cases of HTT collected from September 2001 to December 2018, 18 cases had concomitant cytopathology. Cytological cases were processed with liquid-based cytology (LBC). Immunocytochemistry for HBME-1 and galectine-3 as well as molecular testing for BRAF V600E mutation were performed on both LBC and histological specimens., Results: The 18 lesions with fine needle aspirate cytology ranged in size from 5 to 45 mm. Cytological diagnoses included: 1 benign lesion favoring goiter (5.5%), 4 atypia of undetermined significance (22.2%), 6 follicular neoplasms (33.3%), 5 suspicious for malignancy favoring papillary thyroid cancer (28%), and 2 malignant (11%). Hence, 89% HTT had a negative concordant immunopanel, and they were 100% wild-type BRAF V600E ., Conclusion: The majority of our HTTs (83.3%) were diagnosed in the indeterminate Bethesda categories, suggesting that their cytomorphological features pose issues for reaching a conclusive cytological diagnosis. The ancillary test results in our series support the fact that HTT is a benign neoplasm., (© 2019 American Cancer Society.)

Background: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) is a 6-tier diagnostic category system with associated risks of malignancy (ROMs) and management recommendations. Submandibular gland fine-needle aspiration (FNA) is uncommon with a higher frequency of inflammatory lesions and a higher relative proportion of malignancy, and this may affect the ROM and subsequent management. This study evaluated the application of the MSRSGC and the ROM for each diagnostic category for 734 submandibular gland FNAs., Methods: Submandibular gland FNA cytology specimens from 15 international institutions (2013-2017) were retrospectively assigned to an MSRSGC diagnostic category as follows: nondiagnostic, nonneoplastic, atypia of undetermined significance (AUS), benign neoplasm, salivary gland neoplasm of uncertain malignant potential (SUMP), suspicious for malignancy (SM), or malignant. A correlation with the available histopathologic follow-up was performed, and the ROM was calculated for each MSRSGC diagnostic category., Results: The case cohort of 734 aspirates was reclassified according to the MSRSGC as follows: nondiagnostic, 21.4% (0%-50%); nonneoplastic, 24.2% (9.1%-53.6%); AUS, 6.7% (0%-14.3%); benign neoplasm, 18.3% (0%-52.5%); SUMP, 12% (0%-37.7%); SM, 3.5% (0%-12.5%); and malignant, 13.9% (2%-31.3%). The histopathologic follow-up was available for 333 cases (45.4%). The ROMs were as follows: nondiagnostic, 10.6%; nonneoplastic, 7.5%; AUS, 27.6%; benign neoplasm, 3.2%; SUMP, 41.9%; SM, 82.3%; and malignant, 93.6%., Conclusions: This multi-institutional study shows that the ROM of each MSRSGC category for submandibular gland FNA is similar to that reported for parotid gland FNA, although the reported rates for the different MSRSGC categories were variable across institutions. Thus, the MSRSGC can be reliably applied to submandibular gland FNA., (© 2019 American Cancer Society.)

Whole slide imaging (WSI) has impacted the practice of pathology in the arenas of education, clinical practice, and research. With digital slides, pathologists can circumvent the limitations of traditional glass. Presently, digital pathology is primarily utilized for second opinion consults, clinical conferences, and education at select academic medical centers, with its mainstream adoption on the rise. However, challenges of adoption for oral pathologists are unique given the highly specialized nature of their work. The hurdles include the high-cost instrumentation and regular maintenance, need for additional training, changes in traditional workflow, and integration with present software. Given these barriers, it remains unclear the extent to which slide scanning and virtual pathology should be adopted by oral pathologists at this conjuncture. This review seeks to shed light on the current state of WSI and analyzes the opportunities and challenges for oral pathology in the rapidly evolving field of digital pathology., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The majority of human papillomavirus (HPV)-associated oropharyngeal carcinomas are squamous cell carcinomas; however, there are rare reports of HPV-associated neuroendocrine carcinomas (HPV-NECs) in the upper aerodigestive tract. The aim of this study was to characterize the diagnostic features of fine-needle aspiration (FNA) cases of head and neck HPV-NEC., Methods: Cytology cases of HPV-NEC were identified over a 3-year period from 2 institutions. Clinical, cytomorphologic, and ancillary test results were evaluated., Results: Five FNA cases of HPV-NEC were identified from 4 patients with cervical lymph node metastases with primaries in the oropharynx (n = 2), nasopharynx (n = 1), and larynx (n = 1). Three cases showed mixed small cell and large cell neuroendocrine morphologies; 1 case was a small cell carcinoma, and the last case appeared as a large cell neuroendocrine carcinoma. All tumors were strongly positive for synaptophysin and p16 and negative for p63/p40. Two cases tested for INSM1 showed diffuse nuclear staining. HPV was confirmed by in situ hybridization in 4 cases, and HPV-18 was detected by polymerase chain reaction in the fifth case. Retinoblastoma (Rb) staining was moderate to weak (5/5), and p53 was weakly positive (5/5)., Conclusions: Head and neck HPV-NEC is a rare, aggressive entity that can show mixed small and large cell features and p16 upregulation; p53 and Rb are variable with limited diagnostic utility. Because p16 positivity can be nonspecific, confirmatory HPV testing is required and may be helpful in determining the primary site for neuroendocrine carcinoma of an unknown primary. The accurate diagnosis of HPV-NEC is also important because of its worse prognosis in comparison with HPV-associated squamous cell carcinoma., (© 2018 American Cancer Society.)

Cytological specimens from thyroid nodules are increasingly being adopted as the first available material for cost effectively managing patients in the era of personalized medicine. Cytology aspirates not only play a central role in providing accurate diagnoses, but are also being collected for ancillary molecular testing. Molecular analysis, including the evaluation of somatic mutations and other genomic alterations, has accordingly become well integrated in the cytological workup of thyroid lesions. Appropriately handled thyroid cytology preparations provide well-preserved and adequately cellular material with improved DNA/RNA quantity. The recent publication of the 2nd edition of The Bethesda System for Reporting Thyroid Cytopathology and the American Thyroid Association guidelines confirm the relevant role of molecular testing in the management of the different subcategories of indeterminate thyroid lesions. This review discusses the role of molecular testing for indeterminate thyroid nodules, including the recent introduction of the noninvasive, encapsulated follicular variant of papillary thyroid carcinoma (FVPTC), known also as noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP)., (© 2018 American Cancer Society.)

Background: After increased requests for biopsies for clinical trials and biomarker research, the University of Pittsburgh Medical Center created a clinical trial research service that partnered pathology, radiology, and medicine to facilitate rapid on-site evaluation (ROSE) of fine-needle aspiration (FNA) and/or core needle biopsy (CNB) samples to confirm the presence of tumor in these studies., Methods: Clinical trial coordinators organized biopsies for patients needing tumor samples for trials, and informed the cytopathology and radiology team. ROSE was performed to confirm the presence of sufficient tumor in FNA specimens and/or touch preparations of CNB., Results: A total of 79 cases from a total of 14 clinical trials were evaluated with ROSE, 77 of which (97%) were for research only. There were 53 cases (67%) from breast/ovarian cancer studies that were initiated between 2008 and 2009, whereas 26 cases (33%) included a variety of other tumors for studies that were started between 2011 and 2014. The majority required CNB samples (60 cases; 76%), 20% of which used an FNA for needle placement before obtaining CNB material and 56% of which had touch preparations of the CNB evaluated without a preceding FNA. The concordance rate for ROSE with final adequacy of the sample was 96% to 100%., Conclusions: The study institution has experienced an increase in the number of clinical trial studies requesting ROSE to confirm the presence of tumor in a variety of malignancies. Cytology laboratories can help with patient care by offering ROSE to determine the adequacy of clinical trial material to minimize the submission of unsatisfactory or nonrepresentative material. Developing a clinical research service enhances communication and the processing of novel research specimens for cancer patients. Cancer Cytopathol 2018. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Background: Salivary gland aspiration cytology is useful in the preoperative management of patients but remains challenging, because of the extensive morphologic overlap of some tumors limits the ability to always determine the presence of malignancy. In response to this challenge, there has been increasing drive to develop a risk-based categorization scheme for salivary gland aspirates. Herein, the authors examine the interobserver variability of 1 such pattern and risk-based system., Methods: Select smears and cell-block sections of 50 salivary gland aspirates from 2 large academic centers were digitally imaged. These scanned slides were independently and blindly reviewed by 4 cytopathologists, and each aspirate was assigned to 1 of the proposed pattern-based categories if it was considered neoplastic by the observer. Interobserver agreement was scored and aggregated risks of malignancy were calculated for cases with available surgical follow-up., Results: In total, 42 samples (84%) were considered neoplastic by at least 2 observers and were scored for interobserver agreement: 10 of 42 (23.8%) had uniform agreement, 14 of 42 (33.3%) had majority agreement, and 5 of 42 (11.9%) had divided agreement. Only 9 of 42 samples (21.4%) had minimal agreement, and 4 of 42 (9.5%) had no agreement. Condensation of similar categories was able to improve interobserver agreement and still maintain stratified risk of malignancy., Conclusions: The proposed pattern-based risk-stratification scheme, which could be implemented with the forthcoming Milan System, has good overall interobserver agreement and successfully stratifies the risk of malignancy. Some simplification is possible to make the system easier to use and improve interobserver agreement while maintaining stratification of risk. Cancer Cytopathol 2017;125:776-85. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Background: Critical values have been well established and accepted in laboratory medicine, but to the authors' knowledge are less well accepted in anatomic pathology. Herein, the authors used a reporting process whereby reports with critical diagnoses were coded to ensure that the patient's clinical team was promptly notified electronically of this finding. The aim of the current study was to determine whether this coding mechanism was used appropriately for critical cytopathology diagnoses in the study health care system., Methods: A retrospective review of the University of Pittsburgh Medical Center anatomic pathology laboratory information system was performed to identify cytopathology reports in which a critical diagnosis code (MedTrak notification/CoPath Tissue Code TC66; TC66) was used from 2011 through 2016. TC66-coded cytopathology reports between 2015 and 2016 were reviewed further to determine whether this code was used appropriately., Results: A total of 1687 TC66-coded cytopathology reports were identified. Between 2015 and 2016, a total of 30 of 46 reports (65%) from academic hospitals and 46 of 441 reports (10%) from community hospitals met the critical diagnoses criteria outlined by institutional policy. The remaining TC66-coded cases were predominantly for new diagnoses of malignancy in patients clinically suspected of having cancer., Conclusions: Use of a code for critical cytopathology diagnoses was found to be occurring increasingly at the study health care system. Pathologists at the academic and community hospitals in the study institution used this code somewhat differently, reflecting the need to satisfy communication with clinicians in different practice settings. Nevertheless, the authors' experiences with using a code for critical diagnoses not only ensured timely patient care but also proposed a model that could be used by other medical specialties to enhance communication and improve quality of care. Cancer Cytopathol 2017;125:726-30. © 2017 American Cancer Society., (© 2017 American Cancer Society.)